Memory is central for our mental and physical lives;pronounced memory disorders have a devastating impact on us and our lives, not only a loss of connections with the outside world but also a loss of self- identity. Our long-term objectives are to decipher molecular, cellular, and neuronal circuit mechanisms underlying memory with emphasis on the function of the hippocampus known to play a crucial role in episodic memory. We strive to increase the fundamental knowledge and thereby help develop scientifically rational diagnostic, preventive, and therapeutic methods for memory disorders. In this proposal, we focus on the roles played by two pairs of hippocampal inputs in specific aspects of episodic learning and memory. In order to identify the essential role of mossy fiber (MF) input and the permissive role of perforant path (PP) input converging on CA3, we aim to generate a new transgenic mouse in which release of the excitatory neurotransmitter, glutamate, is blocked specifically at MF terminals but not at PP terminals in a reversibly inducible manner by virtue of temporally controlled expression of transgenic tetnus toxins. We aim to subject these mice to specifically designed spatial or contextual memory tasks in order to rigorously test the influential ideas put forward on a theoretical basis;the feedforward dentate gyrus-CA3 pathway is crucial for encoding similar episodes into distinct memory representations (pattern separation). We will also subject these transgenic mice to in vivo multielectrode recordings of CA3 and CA1 cells to identify physiological correlates of the putative behavioral deficits at the single and ensemble place cell levels. For the study on the differential roles played by excitatory inputs converging on CA1, we aim to generate the second transgenic mouse in which a blockade of glutamate release is targeted to Schaffer colateral (SC) terminals, keeping the temporoammonic (TA) terminals intact. As above, we will subject these mice to behavioral tasks and in vivo multielectrode recordings to rigorously test the ideas that SC input is crucial for retrieving an episodic memory with partial recall cues (pattern completion) as well as for its rapid acquisition. In the US alone 4 million people suffer from Alzheimer's disease (AD). To understand how mnemonic processes are disrupted in AD, it is important to identify the relative contributions of the various alternative hippocampal circuits to memory. The present proposal serves this purpose using cutting edge technologies.